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NO338621B1 - Combinations comprising antimuscarinic agents and corticosteroids - Google Patents

Combinations comprising antimuscarinic agents and corticosteroids Download PDF

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Publication number
NO338621B1
NO338621B1 NO20065482A NO20065482A NO338621B1 NO 338621 B1 NO338621 B1 NO 338621B1 NO 20065482 A NO20065482 A NO 20065482A NO 20065482 A NO20065482 A NO 20065482A NO 338621 B1 NO338621 B1 NO 338621B1
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corticosteroid
antagonist
stated
hydroxy
combination
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NO20065482A
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Norwegian (no)
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NO20065482L (en
Inventor
Hamish Ryder
Jordi Gras Escardo
Jesus Llenas Calvo
Pio Orviz Diaz
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Almirall Sa
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Publication of NO20065482L publication Critical patent/NO20065482L/en
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Description

Foreliggende oppfinnelse vedrører kombinasjoner av (a) kortikosteroider og (b) en antagonist av M3-muskarinreseptorer som er 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan, i form av et salt som har et anion X, som er et farmasøytisk akseptabelt anion av en én- eller flerverdig syre og deres anvendelse ved fremstilling av medikamenter til behandling av respiratoriske forstyrrelser. The present invention relates to combinations of (a) corticosteroids and (b) an antagonist of M3 muscarinic receptors which is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)- 1-azoniabicyclo[2.2.2]octane, in the form of a salt having an anion X, which is a pharmaceutically acceptable anion of a monovalent or polyvalent acid and their use in the manufacture of medicaments for the treatment of respiratory disorders.

BAKGRUNN FOR OPPFINNELSEN BACKGROUND OF THE INVENTION

Kortikosteroider og antimuskarine midler, spesielt antagonister av M3-muskarin-reseptorer, er to klasser av legemidler som er nyttige ved behandling av respiratoriske forstyrrelser, så som astma eller kroniske obstruktive pulmonære sykdommer Corticosteroids and antimuscarinic agents, especially antagonists of M3 muscarinic receptors, are two classes of drugs useful in the treatment of respiratory disorders, such as asthma or chronic obstructive pulmonary diseases

(COPD). (COPD).

Selv om kortikosteroider og antimuskarine midler kan være virksomme terapier, finnes det et klinisk behov for astma- og COPD-terapier som har sterk og selektiv virkning og som haren fordelaktig virkningsprofil. Although corticosteroids and antimuscarinic agents can be effective therapies, there is a clinical need for asthma and COPD therapies that are potent and selective and have beneficial efficacy profiles.

Det er kjent at disse to legemiddelklasser kan brukes i kombinasjoner. Internasjo-nale patentsøknader WO0178736, WO0178739, WO0178741, WO0178743, WO0236106 og WO0247667 beskriver noen eksempler på slike kombinasjoner. It is known that these two drug classes can be used in combinations. International patent applications WO0178736, WO0178739, WO0178741, WO0178743, WO0236106 and WO0247667 describe some examples of such combinations.

Det er kjent at kombinasjoner av legemidler hvor de aktive ingredienser virker via forskjellige fysiologiske baner, er terapeutisk nyttige. Ofte oppstår den terapeutiske fordel fordi kombinasjonen kan oppnå en terapeutisk nyttig virkning ved bruk av lavere konsentrasjoner av hver aktive komponent. Dette gjør det mulig å minimere bivirkningene av medisineringen. Dermed kan kombinasjonen formuleres slik at hver aktive ingrediens foreligger i en konsentrasjon som er subklinisk i andre celler enn de tilsiktede celler i sykdommen. Kombinasjonen er imidlertid terapeutisk virk-som i målceller som reagerer på begge ingrediensene. It is known that combinations of drugs where the active ingredients act via different physiological pathways are therapeutically useful. Often the therapeutic benefit arises because the combination can achieve a therapeutically useful effect using lower concentrations of each active component. This makes it possible to minimize the side effects of the medication. Thus, the combination can be formulated so that each active ingredient is present in a concentration that is subclinical in cells other than the intended cells in the disease. However, the combination is therapeutically effective in target cells that respond to both ingredients.

BESKRIVELSE AV OPPFINNELSEN DESCRIPTION OF THE INVENTION

På overraskende måte kan man observere en uventet fordelaktig terapeutisk virkning ved behandling av inflammatoriske eller obstruktive sykdommer i luftveiene hvis 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan brukes med ett eller flere kortikosteroider. I betraktning av denne virkning kan de farmasøytiske kombinasjoner ifølge oppfinnelsen brukes i mindre doser enn hva som ville være tilfellet med de enkelte forbindelser hvis de ble brukt i monoterapi på vanlig måte, mens de beholder en robust aktivitet i luftveiene. Surprisingly, an unexpectedly beneficial therapeutic effect can be observed in the treatment of inflammatory or obstructive diseases of the respiratory tract if 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)- l-azoniabicyclo[2.2.2]octane is used with one or more corticosteroids. In view of this effect, the pharmaceutical combinations according to the invention can be used in smaller doses than would be the case with the individual compounds if they were used in monotherapy in the usual way, while retaining a robust activity in the respiratory tract.

Foreliggende oppfinnelse tilveiebringer følgelig en kombinasjon som omfatter (a) et kortikosteroid og (b) en antagonist av M3-muskarinreseptorer som er Accordingly, the present invention provides a combination comprising (a) a corticosteroid and (b) an antagonist of M3 muscarinic receptors which is

3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo-[2.2.2]oktan, i form av et salt som har et anion X, som er et farmasøytisk akseptabelt anion av en én- eller flerverdig syre og deres anvendelse ved fremstilling av medikamenter til behandling av respiratoriske forstyrrelser. 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo-[2.2.2]octane, in the form of a salt having an anion X , which is a pharmaceutically acceptable anion of a monovalent or polyvalent acid and their use in the manufacture of medicaments for the treatment of respiratory disorders.

Eksempler på farmasøytisk akseptable anioner av én- eller flerverdige syrer er ani-onene avledet fra uorganiske syrer så som saltsyre, hydrobromsyre, svovelsyre, fosforsyre, eller organiske syrer så som metansulfonsyre, eddiksyre, fumarinsyre, ravsyre, melkesyre, sitronsyre eller maleinsyre. Videre kan blandinger av de ovennevnte syrer brukes. Examples of pharmaceutically acceptable anions of monovalent or polyvalent acids are the anions derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or organic acids such as methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid or maleic acid. Furthermore, mixtures of the above-mentioned acids can be used.

Det er i en utførelsesform spesielt å foretrekke at 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid brukes som M3-antagonist ifølge oppfinnelsen. In one embodiment, it is particularly preferred that 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide is used as M3 -antagonist according to the invention.

Foreliggende oppfinnelse tilveiebringer følgelig en kombinasjon som omfatter (a) et kortikosteroid og (b) en antagonist av M3-muskarinreseptorer som er 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]-oktan, i form av et salt som har et anion X, som er et farmasøytisk akseptabelt anion av en én- eller flerverdig syre. Vanligvis er antagonisten av M3-muskarin-reseptorer 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid. Accordingly, the present invention provides a combination comprising (a) a corticosteroid and (b) an antagonist of M3 muscarinic receptors which is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3 -phenoxypropyl)-1-azoniabicyclo[2.2.2]-octane, in the form of a salt having an anion X, which is a pharmaceutically acceptable anion of a mono- or polyhydric acid. Typically, the antagonist of M3 muscarinic receptors is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide.

Vanligvis inneholder kombinasjonen de aktive ingredienser (a) og (b) som utgjør en del av én enkelt farmasøytisk sammensetning. Generally, the combination contains the active ingredients (a) and (b) which form part of a single pharmaceutical composition.

For å unngå tvil, kan formlene som avbildes ovenfor, og begrepet 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan omfatte saltene i dissosiert, delvis dissosiert eller udissosiert form, f.eks. i vandig oppløsning. De forskjellige salter av forbindelsen kan foreligge i form av solvater, dvs. i form av hydrater, og alle disse former ligger også innen rammen for forelig gende oppfinnelse. Videre kan de forskjellige salter og solvater av forbindelsen foreligge i amorf form eller i form av forskjellige polymorfer innen rammen for foreliggende oppfinnelse. For the avoidance of doubt, the formulas depicted above and the term 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2] octane include the salts in dissociated, partially dissociated or undissociated form, e.g. in aqueous solution. The various salts of the compound can exist in the form of solvates, i.e. in the form of hydrates, and all these forms are also within the scope of the present invention. Furthermore, the various salts and solvates of the compound can be present in amorphous form or in the form of various polymorphs within the scope of the present invention.

Det tilveiebringes også et produkt omfattende (a) et kortikosteroid og (b) en antagonist av M3-muskarinreseptorer som er 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan i form av et salt som har et anion X, som er et farmasøytisk akseptabelt anion av en én- eller flerverdig syre (spesielt 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid), som et kombinasjonspreparat for simultan, atskilt eller sekvensiell bruk ved behandling av et menneske eller et dyr. Vanligvis er produktet for simultan, atskilt eller sekvensiell bruk ved behandling av en respiratorisk sykdom som reagerer på M3-antagonisme i et menneske eller et dyr. Also provided is a product comprising (a) a corticosteroid and (b) an antagonist of M3 muscarinic receptors which is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl )-1-azoniabicyclo[2.2.2]octane in the form of a salt having an anion X which is a pharmaceutically acceptable anion of a mono- or polyhydric acid (in particular 3(R)-(2-hydroxy-2,2 -dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide), as a combination preparation for simultaneous, separate or sequential use in the treatment of a human or an animal. Generally, the product is for simultaneous, separate or sequential use in the treatment of a respiratory disease responsive to M3 antagonism in a human or animal.

Foreliggende oppfinnelse tilveiebringer dessuten anvendelse av (a) et kortikosteroid og (b) en antagonist av M3-muskarinreseptorer som er 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan i form av et salt som har et anion X, som er et farmasøytisk akseptabelt anion av en én- eller flerverdig syre (spesielt 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid), for fremstilling av et legemiddel for simultan, parallell, atskilt eller sekvensiell bruk ved behandling av en respiratorisk sykdom som reagerer på M3-antagonisme i et menneske eller et dyr. The present invention also provides the use of (a) a corticosteroid and (b) an antagonist of M3 muscarinic receptors which is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl )-1-azoniabicyclo[2.2.2]octane in the form of a salt having an anion X which is a pharmaceutically acceptable anion of a mono- or polyhydric acid (in particular 3(R)-(2-hydroxy-2,2 -dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide), for the preparation of a medicament for simultaneous, parallel, separate or sequential use in the treatment of a respiratory disease responsive to M3 antagonism in a human or animal.

Oppfinnelsen tilveiebringer også slik anvendelse av 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan i form av et salt som har et anion X, som er et farmasøytisk akseptabelt anion av en én- eller flerverdig syre (spesielt 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid), for fremstilling av et legemiddel for bruk ved behandling av en respiratorisk sykdom som reagerer på M3-antagonisme i et menneske eller et dyr, ved simultan, ledsagende, atskilt eller sekvensiell koadminist-rasjon med (a) et kortikosteroid. The invention also provides such use of 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane in the form of a salt which has an anion X, which is a pharmaceutically acceptable anion of a mono or polyhydric acid (in particular 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1 -azoniabicyclo[2.2.2]octane bromide), for the manufacture of a medicament for use in the treatment of a respiratory disease responsive to M3 antagonism in a human or an animal, by simultaneous, concomitant, separate or sequential co-administration with (a ) a corticosteroid.

Vanligvis er den respiratoriske sykdom astma, akutt eller kronisk bronkitt, emfysem, kronisk obstruktiv pulmonær sykdom (COPD), bronkial hyperreaktivitet eller rhinitt, spesielt astma eller kronisk obstruktiv pulmonær sykdom (COPD). Usually the respiratory disease is asthma, acute or chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD), bronchial hyperreactivity or rhinitis, especially asthma or chronic obstructive pulmonary disease (COPD).

Fortrinnsvis er pasienten et menneske. Preferably, the patient is a human.

Kombinasjonen beskrevet ovenfor kan inkluderes i en farmasøytisk sammensetning omfattende (a) et kortikosteroid; og (b) en antagonist av M3-muskarinreseptorer som er 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azonia-bicyklo[2.2.2]oktan i form av et salt som har et anion X, som er et farmasøytisk akseptabelt anion av en én- eller flerverdig syre (spesielt 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid), i forbindelse med en farmasøytisk akseptabel bærer eller et fortynningsmiddel. The combination described above can be included in a pharmaceutical composition comprising (a) a corticosteroid; and (b) an antagonist of M3 muscarinic receptors which is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azonia-bicyclo[2.2.2 ]octane in the form of a salt having an anion X which is a pharmaceutically acceptable anion of a mono or polyhydric acid (in particular 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1 -(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide), in association with a pharmaceutically acceptable carrier or diluent.

Dessuten tilveiebringes en pakke omfattende (b) en antagonist av M3-muskarin-reseptorer som er 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan i form av et salt som har et anion X, som er et farma-søytisk akseptabelt anion av en én- eller flerverdig syre (spesielt 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid), og (a) et kortikosteroid for simultan, parallell, atskilt eller sekvensiell bruk ved behandling av en respiratorisk sykdom som reagerer på M3-antagonisme, som angitt i krav 15. Also provided is a kit comprising (b) an antagonist of M3 muscarinic receptors which is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo [2.2.2]octane in the form of a salt having an anion X which is a pharmaceutically acceptable anion of a mono- or polyhydric acid (in particular 3(R)-(2-hydroxy-2,2-dithiene- 2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide), and (a) a corticosteroid for simultaneous, parallel, separate or sequential use in the treatment of a respiratory disease responsive to M3- antagonism, as set forth in claim 15.

Dessuten tilveiebringes en kombinasjon, et produkt, eller en pakke som beskrevet ovenfor, hvor kombinasjonen, produktet, eller pakken ytterligere omfatter (c) en annen aktiv forbindelse valgt fra: (a) PDE IV-inhibitorer, (b) |32-agon ister, (c) leukotrien-D4-antagonister, (d) inhibitorer av egfr-kinase, (e) p38-kinaseinhibitorer og (f) NKl-reseptoragonister, for simultan, atskilt eller sekvensiell bruk. Vanligvis er den ytterligere aktive forbindelse (c) valgt fra gruppen omfattende (a) PDE IV-inhibitorer og (b) |32-agonister. Also provided is a combination, product, or package as described above, wherein the combination, product, or package further comprises (c) another active compound selected from: (a) PDE IV inhibitors, (b) |32-agonists , (c) leukotriene D4 antagonists, (d) egfr kinase inhibitors, (e) p38 kinase inhibitors and (f) NK1 receptor agonists, for simultaneous, separate or sequential use. Typically, the additional active compound (c) is selected from the group comprising (a) PDE IV inhibitors and (b) β 2 agonists.

En utførelse av foreliggende oppfinnelse er at kombinasjonen, produktet, eller pakken omfatter (b) en antagonist av M3-muskarinreseptorer som er 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]-oktan, i form av et salt som har et anion X, som er et farmasøytisk akseptabelt anion av en én- eller flerverdig syre (spesielt 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid), og (a) et kortikosteroid som eneste aktive forbindelser. An embodiment of the present invention is that the combination, product or package comprises (b) an antagonist of M3 muscarinic receptors which is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3 -phenoxypropyl)-1-azoniabicyclo[2.2.2]-octane, in the form of a salt having an anion X, which is a pharmaceutically acceptable anion of a mono- or polyhydric acid (in particular 3(R)-(2-hydroxy -2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide), and (a) a corticosteroid as the only active compounds.

En utførelse av foreliggende oppfinnelse er også anvendelse av b) en antagonist av M3-muskarinreseptorer som er 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan, i form av et salt som har et anion X, som er et farmasøytisk akseptabelt anion av en én- eller flerverdig syre (spesielt 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo- An embodiment of the present invention is also the use of b) an antagonist of M3 muscarinic receptors which is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1- azoniabicyclo[2.2.2]octane, in the form of a salt having an anion X, which is a pharmaceutically acceptable anion of a mono or polyhydric acid (in particular 3(R)-(2-hydroxy-2,2-dithien- 2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo-

[2.2.2]oktanbromid), og (a) et kortikosteroid uten noen annen aktiv forbindelse, for fremstilling av et legemiddel for simultan, parallell, atskilt eller sekvensiell bruk ved behandling av en respiratorisk sykdom som reagerer på M3-antagonisme i et menneske eller et dyr. [2.2.2]octane bromide), and (a) a corticosteroid without any other active compound, for the manufacture of a medicament for simultaneous, parallel, separate or sequential use in the treatment of a respiratory disease responsive to M3 antagonism in a human or an animal.

De foretrukne kortikosteroider for anvendelse i kombinasjonene ifølge oppfinnelsen, er prednisolon, metylprednisolon, deksametason, naflokort, deflazakort, halopredo-nacetat, budesonid, beklometasondipropionat, hydrokortison, triamcinolonacetonid, fluocinolonacetonid, fluocinonid, klokortolonpivalat, metylprednisolonaceponat, dek-sametasonpalmitoat, tipredan, hydrokortisonaceponat, prednikarbat, alklometa-sondipropionat, halometason, metylprednisolonsuleptanat, mometasonfuroat, rimexolon, prednisolonfarnesylat, ciklesonid, deprodonpropionat, flutikasonpropionat, halobetasolpropionat, loteprednoletabonat, betametasonbutyratpropionat, flunisolid, prednison, deksametasonnatriumfosfat, triamcinolon, betametason-17-valerat, betametason, betametasondipropionat, hydrokortisonacetat, hydrokorti-sonnatriumsuksinat, prednisolonnatriumfosfat og hydrokortisonprobutat. The preferred corticosteroids for use in the combinations according to the invention are prednisolone, methylprednisolone, dexamethasone, naflocort, deflazacort, halopredone acetate, budesonide, beclomethasone dipropionate, hydrocortisone, triamcinolone acetonide, fluocinolone acetonide, fluocinonide, clocortolone pivalate, methylprednisolone aceponate, dexamethasone palmitoate, tipredan, hydrocortisone aceponate, prednicarbate , alclomethasone dipropionate, halomethasone, methylprednisolone suleptanate, mometasone furoate, rimexolone, prednisolone farnesylate, ciclesonide, deprodone propionate, fluticasone propionate, halobetasol propionate, loteprednoletabonate, betamethasone butyrate propionate, flunisolide, prednisone, dexamethasone sodium phosphate, triamcinolone, betamethasone-17-valerate, betamethasone, betamethasone dipropionate, hydrocortisone acetate, hydrocortisone sodium succinate , prednisolone sodium phosphate and hydrocortisone probutate.

Spesielt foretrukne kortikosteroider ifølge foreliggende oppfinnelse er: deksametason, budesonid, beklometason, triamcinolon, deksametason, mometason, ciklesonid, flutikason, flunisolid, deksametasonnatriumfosfat og estere derav, samt 6a,9a-difluor-17a-[(2-furanylkarbonyl)oksy]-lip-hydroksy-16a-metyl-3-oksoandrosta-l,4-dien-17p-karbotiolsyre-(S)-fluormetylester. Particularly preferred corticosteroids according to the present invention are: dexamethasone, budesonide, beclomethasone, triamcinolone, dexamethasone, mometasone, ciclesonide, fluticasone, flunisolide, dexamethasone sodium phosphate and esters thereof, as well as 6a,9a-difluoro-17a-[(2-furanylcarbonyl)oxy]-lip -hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothiolic acid (S)-fluoromethyl ester.

Enda mer foretrukne kortikosteroider ifølge foreliggende oppfinnelse er: budesonid, beklometasondipropionat, mometasonfuroat, ciklesonid, triamcinolon, triamcinolonacetonid, triamcinolonheksaacetonid og flutikasonpropionat, valgfritt i form av sine racemater, sine enantiomerer, sine diastereomerer og blandinger derav, og valgfritt deres farmakologisk kompatible syreaddisjonssalter. Enda mer foretrukne er budesonid, beklometasondipropionat, mometasonfuroat, ciklesonid og flutikasonpropionat. De mest foretrukne kortikosteroider ifølge foreliggende oppfinnelse er budesonid og beklometasondipropionat. Even more preferred corticosteroids according to the present invention are: budesonide, beclometasone dipropionate, mometasone furoate, ciclesonide, triamcinolone, triamcinolone acetonide, triamcinolone hexaacetonide and fluticasone propionate, optionally in the form of their racemates, their enantiomers, their diastereomers and mixtures thereof, and optionally their pharmacologically compatible acid addition salts. Even more preferred are budesonide, beclometasone dipropionate, mometasone furoate, ciclesonide and fluticasone propionate. The most preferred corticosteroids according to the present invention are budesonide and beclomethasone dipropionate.

Enhver henvisning til kortikosteroider innen rammen for foreliggende oppfinnelse omfatter også en henvisning til salter eller derivater derav som kan dannes av kortikosteroidene. Eksempler på mulige salter eller derivater omfatter: natriumsal-ter, sulfobenzoater, fosfater, ison i koti nater, acetater, propionater, dihydrogenfosfa-ter, palmitater, pivaiater, farnesylater, aceponater, suleptanater, prednikarbater, furoater eller acetonider. I enkelte tilfeller kan kortikosteroidene også foreligge i form av sine hydrater. Any reference to corticosteroids within the scope of the present invention also includes a reference to salts or derivatives thereof which can be formed from the corticosteroids. Examples of possible salts or derivatives include: sodium salts, sulfobenzoates, phosphates, isoin cotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivaiates, farnesylates, aceponates, suleptanates, prednicarbates, furoates or acetonides. In some cases, the corticosteroids can also be present in the form of their hydrates.

En foretrukken utførelse av foreliggende oppfinnelse er en kombinasjon av en antagonist av M3-muskarinreseptorer som er 3(R)-(2-hydroksy-2,2-ditien-2-ylacet-oksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan, i form av et salt som har et anion X, som er et farmasøytisk akseptabelt anion av en én- eller flerverdig syre (spesielt 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid), med et kortikosteroid valgt fra budesonid, beklometasondipropionat, mometasonfuroat, ciklesonid og flutikasonpropionat. A preferred embodiment of the present invention is a combination of an antagonist of M3 muscarinic receptors which is 3(R)-(2-hydroxy-2,2-dithien-2-ylacet-oxy)-1-(3-phenoxypropyl)-1 -azoniabicyclo[2.2.2]octane, in the form of a salt having an anion X, which is a pharmaceutically acceptable anion of a mono or polyhydric acid (in particular 3(R)-(2-hydroxy-2,2-dithiene -2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide), with a corticosteroid selected from budesonide, beclometasone dipropionate, mometasone furoate, ciclesonide and fluticasone propionate.

En annen utførelse av foreliggende oppfinnelse er en kombinasjon av en M3-antagonist valgt fra gruppen omfattende 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid, og (3R)-3-[(2S)-2-cyklopentyl-2-hydroksy-2-tien-2-ylacetoksy]-l-(2-fenoksyetyl)-l-azoniabicyklo[2.2.2]oktanbromid med et kortikosteroid valgt fra budesonid, beklometasondipropionat, mometasonfuroat, ciklesonid og flutikasonpropionat. Another embodiment of the present invention is a combination of an M3 antagonist selected from the group comprising 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo [2.2.2]octane bromide, and (3R)-3-[(2S)-2-cyclopentyl-2-hydroxy-2-thien-2-ylacetoxy]-1-(2-phenoxyethyl)-1-azoniabicyclo[2.2. 2]octane bromide with a corticosteroid selected from budesonide, beclometasone dipropionate, mometasone furoate, ciclesonide and fluticasone propionate.

I henhold til én utførelse av oppfinnelsen, er antagonisten av M3-muskarin-reseptorer 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan, i form av et salt som har et anion X, som er et farma-søytisk akseptabelt anion av en én- eller flerverdig syre (spesielt 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid), og kortikosteroidet er et beklometasonderivat, spesielt beklometasondipropionat. According to one embodiment of the invention, the antagonist of M3 muscarinic receptors is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2 .2]octane, in the form of a salt having an anion X, which is a pharmaceutically acceptable anion of a mono- or polyhydric acid (especially 3(R)-(2-hydroxy-2,2-dithien-2 -ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide), and the corticosteroid is a beclomethasone derivative, particularly beclomethasone dipropionate.

I henhold til en annen utførelse av oppfinnelsen, er antagonisten av M3-muskarin-reseptorer 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan, i form av et salt som har et anion X, som er et farma-søytisk akseptabelt anion av en én- eller flerverdig syre (spesielt 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid), og kortikosteroidet er budesonid. According to another embodiment of the invention, the antagonist of M3 muscarinic receptors is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[ 2.2.2]octane, in the form of a salt having an anion X, which is a pharmaceutically acceptable anion of a mono- or polyhydric acid (in particular 3(R)-(2-hydroxy-2,2-dithiene- 2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide), and the corticosteroid is budesonide.

Kombinasjonene ifølge oppfinnelsen kan valgfritt omfatte én eller flere ytterligere aktive substanser som er kjent for å være nyttige ved behandling av respiratoriske forstyrrelser, så som PDE4-inhibitorer, fJ2-agonister eller glukokortikoider, leukotrien-D4-inhibitorer, inhibitorer av egfr-kinase, p38-kinaseinhibitorer og/eller NK1-reseptorantagonister. The combinations according to the invention may optionally include one or more additional active substances known to be useful in the treatment of respiratory disorders, such as PDE4 inhibitors, fJ2 agonists or glucocorticoids, leukotriene D4 inhibitors, inhibitors of egfr-kinase, p38 -kinase inhibitors and/or NK1 receptor antagonists.

Eksempler på egnede PDE4-inhibitorer som kan kombineres med M3-antagonister og kortikosteroider, er denbufyllin, rolipram, cipamfyllin, arofyllin, filaminast, picla-milast, mesopram, drotaverinhydroklorid, lirimilast, roflumilast, cilomilast, 6-[2-(3,4-dietoksyfenyl)tiazol-4-yl]pyridin-2-karboksylsyre, (R)-(+)-4-[2-(3-cyklopentyloksy-4-metoksyfenyl)-2-fenyletyl]pyridin, N-(3,5-diklor-4-pyridinyl)-2-[l-(4-fluorbenzyl)-5-hydroksy-lH-indol-3-yl]-2-oksoacetamid, 9-(2-fluorbenzyl)-N6-metyl-2-(trifluormetyl)adenin, N-(3,5-diklor-4-pyridinyl)-8-metoksykinolin-5-karboksamid, N-[9-metyl-4-okso-l-fenyl-3,4,6,7-tetrahydropyrrolo[3,2,l-jk][l,4]-benzodiazepin-3(R)-yl]pyridin-4-karboksamid, 3-[3-(cyklopentyloksy)-4-metoksybenzyl]-6-(etylamino)-8-isopropyl-3H-purinhydroklorid, 4-[6,7-dietoksy-2.3- bis(hydroksymetyl)naftalen-l-yl]-l-(2-metoksyetyl)pyridin-2(lH)-on, 2-karbometoksy-4-cyano-4-(3-cyklopropylmetoksy-4-difluormetoksyfenyl)-cykloheksan-l-on, c/'s-[4-cyano-4-(3-cyklopropylmetoksy-4-difluormetoksyfenyl)-cyklohexan-l-ol, ONO-6126 (Eur Respir J 2003, 22 (Suppl. 45): Abst 2557) og forbindelsene som beskrives i PCT-patentsøknadene nr. WO03/097613 og PCT/EP03/14722 og i spansk patentsøknad nr. P200302613. Examples of suitable PDE4 inhibitors that can be combined with M3 antagonists and corticosteroids are denbuphylline, rolipram, cipamphylline, arophylline, filaminast, picla-milast, mesopram, drotaverine hydrochloride, lirimilast, roflumilast, cilomilast, 6-[2-(3,4 -diethoxyphenyl)thiazol-4-yl]pyridine-2-carboxylic acid, (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine, N-(3,5 -dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxoacetamide, 9-(2-fluorobenzyl)-N6-methyl-2- (trifluoromethyl)adenine, N-(3,5-dichloro-4-pyridinyl)-8-methoxyquinoline-5-carboxamide, N-[9-methyl-4-oxo-l-phenyl-3,4,6,7- tetrahydropyrrolo[3,2,1-jk][1,4]-benzodiazepine-3(R)-yl]pyridin-4-carboxamide, 3-[3-(cyclopentyloxy)-4-methoxybenzyl]-6-(ethylamino) -8-isopropyl-3H-purine hydrochloride, 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-methoxyethyl)pyridin-2(1H)-one, 2-carbomethoxy -4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-cyclohexan-1-one, c/'s-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromet oxyphenyl)-cyclohexan-l-ol, ONO-6126 (Eur Respir J 2003, 22 (Suppl. 45): Abst 2557) and the compounds described in PCT Patent Applications No. WO03/097613 and PCT/EP03/14722 and in Spanish Patent Application No. P200302613.

Eksempler på egnede p2-agonister som kan kombineres med M3-antagonister og kortikosteroider, er: arformoterol, bambuterol, bitolterol, broksaterol, karbuterol, klenbuterol, dopeksamin, fenoterol, formoterol, heksoprenalin, ibuterol, isoetarin, isoprenalin, levosalbutamol, mabuterol, meluadrin, metaprotenerol, nolomirol, orci-prenalin, pirbuterol, prokaterol, reproterol, ritodrin, rimoterol, salbutamol, salmefamol, salmeterol, sibenadet, sotenerot, sulfonterol, terbutalin, tiaramid, tulobuterol, GSK-597901, GSK-159797, GSK-678007, GSK-642444, GSK-159802, HOKU-81, (-)-2-[7(S)-[2(R)-hydroksy-2-(4-hydroksyfenyl)etylamino]-5,6,7,8-tetrahydro-2-naftyloksy]-N,N-dimetylacetamidhydrokloridmonohydrat, karmoterol, QAB-149 og 5-[2-(5,6-dietylindan-2-ylamino)-l-hydroksyetyl]-8-hydroksy-lH-kinolin-2-on, 4-hydroksy-7-[2-{[2-{[3-(2-fenyletoksy)propyl]sulfonyl}etyl]amino}-etyl]-2(3H)-benzotiazolon, l-(2-fluor-4-hydroksyfenyl)-2-[4-(l-benzimidazolyl)-2-metyl-2-butylamino]etanol, l-[3-(4-metoksybenzylamino)-4-hydroksyfenyl]-2-[4-(l-benzimidazolyl)-2-metyl-2-butylamino]etanol, l-[2H-5-hydroksy-3-okso-4H-l,4-benzoksazin-8-yl]-2-[3-(4-N,N-dimetylaminofenyl)-2-metyl-2-propylamino]etanol, 1- [2H-5-hydroksy-3-okso-4H-l,4-benzoksazin-8-yl]-2-[3-(4-metoksyfenyl)-2-metyl-2-propylamino]etanol, l-[2H-5-hydroksy-3-okso-4H-l,4-benzoksazin-8-yl]-2- [3-(4-n-butyloksyfenyl)-2-metyl-2-propylamino]etanol, l-[2H-5-hydroksy-3-okso-4H-l,4-benzoksazin-8-yl]-2-{4-[3-(4-metoksyfenyl)-l,2,4-triazol-3-yl]-2-metyl-2-butylamino}etanol, 5-hydroksy-8-(l-hydroksy-2-isopropylaminobutyl)-2H-1.4- benzoksazin-3-(4H)-on, l-(4-amino-3-klor-5-trifluormetylfenyl)-2-tert- butylamino)etanol og l-(4-etoksykarbonylamino-3-cyano-5-fluorfenyl)-2-(tert-butylamino)etanol, valgfritt i form av sine racemater, sine enantiomerer, sine diastereomerer, og blandinger derav, og valgfritt deres farmakologisk kompatible syreaddisjonssalter. Examples of suitable p2 agonists that can be combined with M3 antagonists and corticosteroids are: arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, dopexamine, fenoterol, formoterol, hexoprenaline, ibuterol, isoetarine, isoprenaline, levosalbutamol, mabuterol, meluadrin, metaprotenerol, nolomirol, orci-prenaline, pirbuterol, procaterol, reproterol, ritodrine, rimoterol, salbutamol, salmefamol, salmeterol, sibenadet, sotenerot, sulfonterol, terbutaline, thiaramide, tulobuterol, GSK-597901, GSK-159797, GSK-678007, GSK- 642444, GSK-159802, HOKU-81, (-)-2-[7(S)-[2(R)-hydroxy-2-(4-hydroxyphenyl)ethylamino]-5,6,7,8-tetrahydro- 2-naphthyloxy]-N,N-dimethylacetamide hydrochloride monohydrate, carmoterol, QAB-149 and 5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one , 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}-ethyl]-2(3H)-benzothiazolone, l-(2-fluoro-4 -hydroxyphenyl)-2-[4-(l-benzimidazolyl)-2-methyl-2-butylamino]ethanol, l-[3-(4-methoxybenzylami no)-4-hydroxyphenyl]-2-[4-(l-benzimidazolyl)-2-methyl-2-butylamino]ethanol, l-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine- 8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1- [2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine -8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, l-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazine-8- yl]-2- [3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl ]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy- 2-isopropylaminobutyl)-2H-1,4- benzoxazin-3-(4H)-one, l-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol and l-(4-ethoxycarbonylamino- 3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol, optionally in the form of its racemates, its enantiomers, its diastereomers, and mixtures thereof, and optionally their pharmacologically compatible acid addition salts.

Eksempler på egnede LTD4-antagonister som kan kombineres med M3-antagonister og kortikosteroider, er tomelukast, Ibudilast, pobilukast, pranlukasthydrat, zafirlu-kast, ritolukast, verlukast, sulukast, cinalukast, iralukastnatrium, montelukastna-trium, 4-[4-[3-(4-acetyl-3-hydroksy-2-propylfenoksy)propylsulfonyl]fenyl]-4-oksosmørsyre, [[5-[[3-(4-acetyl-3-hydroksy-2-propylfenoksy)propyl]tio]-l,3,4-tia-diazol-2-yl]tio]eddiksyre, 9-[(4-acetyl-3-hydroksy-2-n-propylfenoksy)metyl]-3-(lH-tetrazol-5-yl)-4H-pyrido[l,2-a]pyrimidin-4-on, 5-[3-[2-(7-klorkinolin-2-yl)vinyl]-fenyl]-8-(N,N-dimetylkarbamoyl)-4,6-ditiaoktansyrenatriumsalt; 3-[l-[3-[2-(7-klorkinolin-2-yl)vinyl]fenyl]-l-[3-(dimetylamino)-3-oksopropylsulfanyl]-metylsulfanyl]propionsyrenatriumsalt, 6-(2-cykloheksyletyl)-[l,3,4]tiadiazolo-[3,2-a]-l,2,3-triazolo[4,5-d]pyrimidin-9(lH)-on, 4-[6-acetyl-3-[3-(4-acetyl-3-hydroksy-2-propylfenyltio)propoksy]-2-propylfenoksy]smørsyre, (R)-3-metoksy-4-[l-metyl-5-[N-(2-metyl-4,4,4-trifluorbutyl)karbamoyl]indol-3-ylmetyl]-N-(2-metylfenylsulfonyl)benzamid, (R)-3-[2-metoksy-4-[N-(2-metylfenylsulfonyl)-karbamoyl]benzyl]-l-metyl-N-(4,4,4-trifluor-2-metylbutyl)indol-5-karboksamid, (+)-4(S)-(4-karboksyfenyltio)-7-[4-(4-fenoksybutoksy)fenyl]-5(Z)-heptensyre og forbindelsene som beskrives i PCT-patentsøknad nr. PCT/EP03/12581. Examples of suitable LTD4 antagonists that can be combined with M3 antagonists and corticosteroids are tomelukast, Ibudilast, pobilukast, pranlukast hydrate, zafirlukast, ritolukast, verlukast, sulukast, cinalukast, iralukast sodium, montelukast sodium, 4-[4-[3 -(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]phenyl]-4-oxobutyric acid, [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-l ,3,4-thia-diazol-2-yl]thio]acetic acid, 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-(1H-tetrazol-5-yl)- 4H-pyrido[1,2-a]pyrimidin-4-one, 5-[3-[2-(7-chloroquinolin-2-yl)vinyl]-phenyl]-8-(N,N-dimethylcarbamoyl)-4 ,6-dithiooctanoic acid sodium salt; 3-[1-[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-1-[3-(dimethylamino)-3-oxopropylsulfanyl]-methylsulfanyl]propionic acid sodium salt, 6-(2-cyclohexylethyl) -[1,3,4]thiadiazolo-[3,2-a]-1,2,3-triazolo[4,5-d]pyrimidin-9(1H)-one, 4-[6-acetyl-3- [3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]butyric acid, (R)-3-methoxy-4-[1-methyl-5-[N-(2-methyl- 4,4,4-trifluorobutyl)carbamoyl]indol-3-ylmethyl]-N-(2-methylphenylsulfonyl)benzamide, (R)-3-[2-methoxy-4-[N-(2-methylphenylsulfonyl)-carbamoyl] benzyl]-1-methyl-N-(4,4,4-trifluoro-2-methylbutyl)indole-5-carboxamide, (+)-4(S)-(4-carboxyphenylthio)-7-[4-(4 -phenoxybutoxy)phenyl]-5(Z)-heptenoic acid and the compounds described in PCT Patent Application No. PCT/EP03/12581.

Eksempler på egnede inhibitorer av egfr-kinase som kan kombineres med M3-antagonister og kortikosteroider, er palifermin, cetuximab, gefitinib, repifermin, er-lotinibhydroklorid, canertinibdihydroklorid, lapatinib og N-[4-(3-klor-4-fluorfenyl-amino)-3-cyano-7-etoksykinolin-6-yl]-4-(dimetylamino)-2(E)-butenamid. Examples of suitable egfr-kinase inhibitors that can be combined with M3 antagonists and corticosteroids are palifermin, cetuximab, gefitinib, repifermin, erlotinib hydrochloride, canertinib dihydrochloride, lapatinib and N-[4-(3-chloro-4-fluorophenyl-amino) )-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)-2(E)-butenamide.

Eksempler på egnede p38-kinaseinhibitorer som kan kombineres med M3-antagonister og kortikosteroider, er klormetiazoledisylat, doramapimod, 5-(2,6-diklorfenyl)-2-(2,4-difluorfenylsulfanyl)-6H-pyrimido[3,4-b]pyridazin-6-on, 4-acetamido-N-(tert-butyl)benzamid, SCIO-469 (beskrevet i Clin Pharmacol Ther 2004, 75 (2): Abst PII-7) og VX-702 beskrevet i Circulation 2003, 108 (17, Suppl. Examples of suitable p38-kinase inhibitors that can be combined with M3 antagonists and corticosteroids are chlormethiazoledisylate, doramapimod, 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenylsulfanyl)-6H-pyrimido[3,4-b ]pyridazin-6-one, 4-acetamido-N-(tert-butyl)benzamide, SCIO-469 (described in Clin Pharmacol Ther 2004, 75 (2): Abst PII-7) and VX-702 described in Circulation 2003, 108 (17, Suppl.

4): Abst 882. 4): Abst 882.

Eksempler på egnede NKl-reseptorantagonister som kan kombineres med M3-antagonister og kortikosteroider, er nolpitantiumbesilat, dapitant, lanepitant, vofopitanthydroklorid, aprepitant, ezlopitant, N-[3-(2-pentylfenyl)propionyl]treonyl- N-metyl-2,3-dehydrotyrosyl-leucyl-D-fenylalanylallotreonylasparaginylserin-C-1.7-0-3.1-lakton, l-metylindol-3-ylkarbonyl-[4(R)-hydroksy]-L-prolyl-[3-(2-naftyl)]-L-alanin-N-benzyl-N-metylamid, (+)-(2S,3S)-3-[2-metoksy-5-(trifluormetoksy)-benzylamino]-2-fenylpiperidin, (2R,4S)-N-[l-[3,5-bis(trifluormetyl)benzoyl]-2-(4-klorbenzyl)piperidin-4-yl]kinolin-4-karboksamid, 3-[2(R)-[l(R)-[3,5-bis-(trifluormetyl)fenyl]etoksy]-3(S)-(4-fluorfenyl)morfolin-4-ylmetyl]-5-okso-4,5-dihydro-lH-l,2,4-triazol-l-fosfinsyre-bis(N-metyl-D-glukamin)salt; [3-[2(R)-[l(R)-[3,5-bis(trifluormetyl)fenyl]etoksy]-3(S)-(4-fluorfenyl)-4-morfolinylmetyl]-2,5-dihydro-5-okso-lH-l,2,4-triazol-l-yl]fosfonsyre-l-deoksy-l-(metylamino)-D-glucitol-(l:2)-salt, l'-[2-[2(R)-(3,4-diklorfenyl)-4-(3,4,5-trimetoksybenzoyl)-morfolin-2-yl]etyl]spiro[benzo[c]tiofen-l(3H)-4'-piperidin]-2(S)-oksidriydroklorid og forbindelsen CS-003 som beskrives i Eur Respir J 2003, 22 (Suppl. 45): Abst P2664. Examples of suitable NK1 receptor antagonists that can be combined with M3 antagonists and corticosteroids are nolpitantium besylate, dapitant, lanepitant, vofopitant hydrochloride, aprepitant, ezlopitant, N-[3-(2-pentylphenyl)propionyl]threonyl-N-methyl-2,3 -dehydrotyrosyl-leucyl-D-phenylalanylallotreonylasparaginylserine-C-1.7-0-3.1-lactone, l-methylindol-3-ylcarbonyl-[4(R)-hydroxy]-L-prolyl-[3-(2-naphthyl)]- L-alanine-N-benzyl-N-methylamide, (+)-(2S,3S)-3-[2-methoxy-5-(trifluoromethoxy)-benzylamino]-2-phenylpiperidine, (2R,4S)-N- [1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-chlorobenzyl)piperidin-4-yl]quinoline-4-carboxamide, 3-[2(R)-[1(R)-[3 ,5-bis-(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)morpholin-4-ylmethyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol- 1-phosphinic acid bis(N-methyl-D-glucamine) salt; [3-[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4-morpholinylmethyl]-2,5-dihydro -5-oxo-1H-1,2,4-triazol-1-yl]phosphonic acid-1-deoxy-1-(methylamino)-D-glucitol-(1:2)-salt, l'-[2-[ 2(R)-(3,4-Dichlorophenyl)-4-(3,4,5-trimethoxybenzoyl)-morpholin-2-yl]ethyl]spiro[benzo[c]thiophene-1(3H)-4'-piperidine ]-2(S)-oxygen hydrochloride and the compound CS-003 described in Eur Respir J 2003, 22 (Suppl. 45): Abst P2664.

Kombinasjonene ifølge oppfinnelsen kan brukes ved behandling av en hvilken som The combinations according to the invention can be used in the treatment of which

helst forstyrrelse som kan lindres ved simultan, parallell eller sekvensiell antagoni-sering av M3-muskarinreseptorer og kortikosteroider. Dermed omfatter foreliggende søknad anvendelse av kombinasjonene ifølge oppfinnelsen ved fremstilling av et legemiddel for behandling av disse forstyrrelser. preferably disorder that can be alleviated by simultaneous, parallel or sequential antagonism of M3 muscarinic receptors and corticosteroids. Thus, the present application includes the use of the combinations according to the invention in the manufacture of a medicinal product for the treatment of these disorders.

Foretrukne eksempler på slike forstyrrelser er slike respiratoriske sykdommer hvor anvendelse av bronkodilatoriske midler forventes å ha en fordelaktig virkning, f.eks. astma, akutt eller kronisk bronkitt, emfysem eller kronisk obstruktiv pulmonær sykdom (COPD), også kjent som kronisk obstruktiv lungesykdom (KOLS). Preferred examples of such disorders are such respiratory diseases where the use of bronchodilators is expected to have a beneficial effect, e.g. asthma, acute or chronic bronchitis, emphysema or chronic obstructive pulmonary disease (COPD), also known as chronic obstructive pulmonary disease (COPD).

De aktive forbindelser i kombinasjonen, dvs. den aktuelle M3-antagonisten, kortikosteroidet og hvilke som helst andre valgfrie aktive forbindelser, kan administreres sammen i én og samme farmasøytiske sammensetning eller i forskjellige sammensetninger som er tenkt for atskilt, simultan, parallell eller sekvensiell administrasjon via samme rute eller forskjellige ruter. The active compounds in the combination, i.e. the relevant M3 antagonist, the corticosteroid and any other optional active compounds, may be administered together in one and the same pharmaceutical composition or in different compositions intended for separate, simultaneous, parallel or sequential administration via same route or different routes.

I en annen utførelse tilveiebringer foreliggende oppfinnelse en pakke omfattende en antagonist av M3-muskarinreseptorer som angitt i krav 1 og et kortikosteroid for simultan, parallell, atskilt eller sekvensiell bruk ved behandling av en respiratorisk sykdom som reagerer på M3-antagonisme. In another embodiment, the present invention provides a package comprising an antagonist of M3 muscarinic receptors as set forth in claim 1 and a corticosteroid for simultaneous, parallel, separate or sequential use in the treatment of a respiratory disease responsive to M3 antagonism.

I en annen utførelse består foreliggende oppfinnelse i en pakke omfattende en antagonist av M3-muskarinreseptorer som er 3(R)-(2-hydroksy-2,2-ditien-2- ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan, i form av et salt som har et anion X, som er et farmasøytisk akseptabelt anion av en én- eller flerverdig syre (spesielt 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid) og et kortikosteroid, for simultan, parallell, atskilt eller sekvensiell bruk ved behandling av en respiratorisk sykdom som reagerer på M3-antagonisme. In another embodiment, the present invention consists in a package comprising an antagonist of M3 muscarinic receptors which is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1- azoniabicyclo[2.2.2]octane, in the form of a salt having an anion X, which is a pharmaceutically acceptable anion of a mono or polyhydric acid (in particular 3(R)-(2-hydroxy-2,2-dithien- 2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide) and a corticosteroid, for simultaneous, parallel, separate or sequential use in the treatment of a respiratory disease responsive to M3 antagonism.

Foretrukket administreres kombinasjonen av de aktive forbindelser ved inhalasjon gjennom en vanlig leveringsanordning, hvor de kan være formulert i samme eller forskjellige farmasøytiske sammensetninger. The combination of the active compounds is preferably administered by inhalation through a conventional delivery device, where they may be formulated in the same or different pharmaceutical compositions.

I den mest foretrukne utførelse foreligger M3-antagonisten og kortikosteroidet i samme farmasøytiske sammensetning og administreres ved inhalasjon gjennom en vanlig leveringsanordning. In the most preferred embodiment, the M3 antagonist and the corticosteroid are in the same pharmaceutical composition and are administered by inhalation through a conventional delivery device.

I ett trekk tilveiebringer oppfinnelsen en kombinasjon som definert heri, kjenneteg-net ved at de aktive ingredienser (a) og (b) utgjør en del av én enkelt farmasøytisk sammensetning. In one feature, the invention provides a combination as defined herein, characterized in that the active ingredients (a) and (b) form part of a single pharmaceutical composition.

De aktive forbindelser i kombinasjonen, dvs. den aktuelle M3-antagonisten, kortikosteroidet og hvilke som helst andre valgfrie aktive forbindelser, kan administreres via en hvilken som helst egnet rute, avhengig av naturen av forstyrrelsen som skal behandles, f.eks. oralt (som sirup, tabletter, kapsler, sugepastiller, preparater med regulert frigivning, raskt oppløselige preparater, sugepastiller osv.); topisk (som kremer, salver, losjoner, nesesprayer eller aerosoler osv.); ved injeksjon (subkutan, intradermisk, intramuskulær, intravenøs osv.) eller ved inhalasjon (som tørrpulver, en oppløsning, en dispersjon osv.). The active compounds in the combination, i.e. the relevant M3 antagonist, the corticosteroid and any other optional active compounds, can be administered by any suitable route depending on the nature of the disorder to be treated, e.g. orally (such as syrup, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, lozenges, etc.); topical (such as creams, ointments, lotions, nasal sprays or aerosols, etc.); by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.) or by inhalation (as a dry powder, a solution, a dispersion, etc.).

De farmasøytiske sammensetninger kan med fordel presenteres i enhetsdoseform og kan fremstilles ved bruk av en hvilken som helst metode som er velkjent innen farmasifaget. Alle metodene omfatter trinnet å bringe den eller de aktive ingredienser i kontakt med bæreren. Generelt fremstilles formuleringene ved å bringe den aktive ingrediens i enhetlig og intim kontakt med flytende bærere eller findelte faste bærere eller begge deler og deretter om nødvendig å forme produktet til den ønskede formulering. The pharmaceutical compositions can advantageously be presented in unit dose form and can be prepared using any method well known in the pharmaceutical art. All methods include the step of bringing the active ingredient(s) into contact with the carrier. In general, the formulations are prepared by bringing the active ingredient into uniform and intimate contact with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Formuleringer som er egnet for oral administrasjon, kan presenteres som atskilte enheter så som kapsler, pulverposer eller tabletter som hver inneholder en forut- bestemt mengde av den aktive ingrediens; som et pulver eller granulat; som en oppløsning eller en suspensjon i en vandig væske eller en ikke-vandig væske; eller som en flytende olje-i-vann-emulsjon eller en flytende vann-i-olje-emulsjon. Den aktive ingrediens kan også presenteres som en boluspille, latverge eller pasta. Formulations suitable for oral administration may be presented as separate units such as capsules, powder sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granule; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as a liquid oil-in-water emulsion or a liquid water-in-oil emulsion. The active ingredient can also be presented as a bolus pill, suppository or paste.

En sirupformulering vil generelt bestå av en suspensjon eller oppløsning av forbindelsen eller saltet i en flytende bærer, f.eks. etanol, naturlige, syntetiske eller halv-syntetiske oljer så som jordnøttolje og olivenolje, glyserin eller vann, med smak-stoffer, søtstoffer og/eller fargestoffer. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier, e.g. ethanol, natural, synthetic or semi-synthetic oils such as peanut oil and olive oil, glycerin or water, with flavourings, sweeteners and/or colours.

Når sammensetningen har form av en tablett, kan en hvilken som helst farmasøy-tisk bærer som rutinemessig brukes til å fremstille faste formuleringer, brukes. Eksempler på slike bærere omfatter cellulose, stearater så som magnesiumstearat eller stearinsyre, talkum, gelatin, akasie, stivelse, melkesukker og sakkarose. When the composition is in the form of a tablet, any pharmaceutical carrier routinely used to prepare solid formulations may be used. Examples of such carriers include cellulose, stearates such as magnesium stearate or stearic acid, talc, gelatin, acacia, starch, milk sugar and sucrose.

En tablett kan fremstilles ved komprimering eller støping, valgfritt med én eller flere hjelpeingredienser. Komprimerte tabletter kan fremstilles ved å komprimere, i en egnet maskin, den aktive ingrediens i frittflytende form så som et pulver eller granulat, valgfritt blandet med bindemidler, smøremidler, inerte fortynningsstoffer, smørende, overflateaktive eller dispergerende midler. Støpte tabletter kan fremstilles ved å støpe, i en egnet maskin, en blanding av pulverblandingen omfattende de aktive forbindelser fuktet med et inert flytende fortynningsmiddel, og valgfritt tør-king og sikting. Tablettene kan valgfritt belegges eller forsynes med skår og kan formuleres slik at de gir en modifisert (dvs. langsom eller regulert) frigivning av den aktive ingrediens som foreligger deri. A tablet can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in free-flowing form such as a powder or granule, optionally mixed with binders, lubricants, inert diluents, lubricating, surface-active or dispersing agents. Molded tablets may be prepared by molding, in a suitable machine, a mixture of the powder mixture comprising the active compounds moistened with an inert liquid diluent, and optionally drying and sieving. The tablets can optionally be coated or provided with chips and can be formulated so that they provide a modified (ie slow or regulated) release of the active ingredient contained therein.

Når sammensetningen har form av en kapsel, er en hvilken som helst rutinemessig innkapsling egnet, f.eks. ved bruk av de ovennevnte bærere i en hårdgelatinkapsel. Når sammensetningen har form av en bløtgelatinkapsel, kan en hvilken som helst farmasøytisk bærer som rutinemessig brukes for fremstilling av dispersjoner eller suspensjoner, tas i betraktning, f.eks. vandige gummier, cellulose, silikater eller oljer, og innlemmes i en bløtgelatinkapsel. When the composition is in the form of a capsule, any routine encapsulation is suitable, e.g. using the above carriers in a hard gelatin capsule. When the composition is in the form of a soft gelatin capsule, any pharmaceutical carrier routinely used for the preparation of dispersions or suspensions may be considered, e.g. aqueous gums, cellulose, silicates or oils, and incorporated into a soft gelatin capsule.

Tørrpulversammensetninger for topisk levering til lungene ved inhalasjon kan f.eks. presenteres i forskjellige primære forpakningssystemer (så som kapsler og patroner av f.eks. gelatin eller kuler (blistere) av f.eks. laminert aluminiumfolie), for bruk i en inhalator eller insufflator. Dry powder compositions for topical delivery to the lungs by inhalation can e.g. are presented in various primary packaging systems (such as capsules and cartridges of e.g. gelatin or pellets (blisters) of e.g. laminated aluminum foil), for use in an inhaler or insufflator.

Forpakningen av formuleringen kan være egnet for enhetsdose- eller flerdoselevering. I tilfellet av flerdoselevering, kan formuleringen være målt opp på forhånd eller måles opp ved bruk. Tørrpulverinhalatorer klassifiseres dermed i tre grupper: The packaging of the formulation may be suitable for unit dose or multiple dose delivery. In the case of multi-dose delivery, the formulation may be premeasured or measured upon use. Dry powder inhalers are thus classified into three groups:

(a) enkeltdose-, (b) flerenhetsdose- og (c) flerdoseanordninger. (a) single-dose, (b) multi-unit dose and (c) multi-dose devices.

Formuleringene inneholder generelt en pulverblanding for inhalasjon av kombinasjonen ifølge oppfinnelsen og en egnet pulverbasis (bærersubstans) så som melkesukker eller stivelse. Anvendelse av melkesukker foretrekkes. Hver kapsel eller pa-tron kan generelt inneholde mellom 2^g og 400^g av hver terapeutisk aktive ingrediens. Alternativt kan den eller de aktive ingredienser presenteres uten eksipienser. The formulations generally contain a powder mixture for inhalation of the combination according to the invention and a suitable powder base (carrier substance) such as milk sugar or starch. The use of milk sugar is preferred. Each capsule or cartridge may generally contain between 2g and 400g of each therapeutically active ingredient. Alternatively, the active ingredient(s) may be presented without excipients.

For enkeltdoseinhalatorer av den første type, har produsenten veid opp enkeltdoser i små beholdere, som for det meste er hårdgelatinkapsler. En kapsel må tas ut fra en atskilt boks eller beholder og innføres i et mottaksparti av inhalatoren. Dernest må kapselen åpnes eller perforeres med nål eller skjæreblad for å gjøre det mulig for en del av den innsugde luftstrøm å passere gjennom kapselen for å fange opp pulver eller å frigi pulver fra kapselen gjennom disse perforasjoner ved hjelp av sentrifugalkrefter under inhalasjonen. Etter inhalasjonen, må den tømte kapsel igjen fjernes fra inhalatoren. For det meste er det nødvendig å ta fra hverandre inhalatoren for å innføre og fjerne kapselen, hvilket er en prosess som kan være vanskelig og anstrengende for enkelte pasienter. Andre ulemper forbundet med bruken av hårdgelatinkapsler for inhalasjonspulvere er (a) dårlig beskyttelse mot opptak av fuktighet fra omgivelsesluften, (b) problemer med å åpne eller perforere etter at kapslene tidligere er blitt utsatt for ekstrem relativ fuktighet, hvilket forår-saker fragmentering eller bulking, og (c) mulig inhalasjon av kapselfragmenter. For et antall kapselinhalatorer er det dessuten blitt rapportert en ufullstendig utstøtning (f.eks. Nielsen et al., 1997). For single dose inhalers of the first type, the manufacturer has weighed up single doses in small containers, which are mostly hard gelatin capsules. A capsule must be removed from a separate box or container and inserted into a receiving part of the inhaler. Next, the capsule must be opened or perforated with a needle or cutting blade to enable a portion of the aspirated airflow to pass through the capsule to capture powder or to release powder from the capsule through these perforations by centrifugal forces during inhalation. After inhalation, the empty capsule must again be removed from the inhaler. In most cases, it is necessary to take the inhaler apart to insert and remove the capsule, which is a process that can be difficult and strenuous for some patients. Other disadvantages associated with the use of hard gelatin capsules for inhalation powders are (a) poor protection against absorption of moisture from the ambient air, (b) difficulty opening or perforating after the capsules have previously been exposed to extreme relative humidity, causing fragmentation or bulking , and (c) possible inhalation of capsule fragments. In addition, incomplete ejection has been reported for a number of capsule inhalers (eg Nielsen et al., 1997).

Enkelte kapselinhalatorer har et magasin fra hvilket kapsler kan overføres enkeltvis til et mottakskammer, hvor perforasjon og tømming finner sted, slik som det beskrives i WO 92/03175. Andre kapselinhalatorer har roterende magasiner med kap-selkammere som kan bringes i linje med luftkanalen for doseutstøtning (f.eks. WO91/02558 og GB 2242134). Sammen med blisterinhalatorer utgjør de den type flerenhetsdoseinhalatorer som har et begrenset antall enhetsdoser på lager på en plate eller en strimmel. Some capsule inhalers have a magazine from which capsules can be transferred individually to a receiving chamber, where perforation and emptying take place, as described in WO 92/03175. Other capsule inhalers have rotary magazines with capsule chambers that can be aligned with the air channel for dose ejection (eg WO91/02558 and GB 2242134). Together with blister inhalers, they form the type of multi-unit dose inhalers that have a limited number of unit doses stored on a plate or strip.

Blisterinhalatorer gir en bedre beskyttelse av legemidlet mot fuktighet enn kapselinhalatorer. Tilgang til pulveret oppnås ved å perforere både skallet og blisterfolien, eller ved å skrelle av dekkfolien. Når det brukes en blisterstrimmel istedenfor en plate, kan antallet doser heves, men det er ubekvemt for pasienten å erstatte en tom strimmel. Derfor skal slike anordninger ofte kastes sammen med det innlem-mede dosesystem, medregnet teknikken som brukes til å transportere strimmelen og åpne blisterlommene. Blister inhalers provide better protection of the medicine against moisture than capsule inhalers. Access to the powder is achieved by perforating both the shell and the blister foil, or by peeling off the cover foil. When a blister strip is used instead of a plate, the number of doses can be increased, but it is inconvenient for the patient to replace an empty strip. Therefore, such devices must often be discarded together with the incorporated dose system, including the technique used to transport the strip and open the blister pockets.

Flerdoseinhalatorer inneholder ikke forhåndsoppmålte mengder pulverformulering. Multi-dose inhalers do not contain pre-measured amounts of powder formulation.

De består av en relativt stor beholder og en doseoppmålingsenhet som må betjenes av pasienten. Beholderen bærer flere doser som isoleres enkeltvis fra pulverbulken ved volumetrisk forskyvning. Det finnes forskjellige doseoppmålingsenheter, omfattende roterbare membraner (f.eks. EP0069715) eller plater (f.eks. GB 2041763; EP 0424790; DE 4239402 og EP 0674533), roterbare sylindere (f.eks. EP 0166294; GB 2165159 og WO 92/09322) og roterbare kjeglestumper (f.eks. WO 92/00771), som alle har hulrom som må fylles med pulver fra beholderen. Andre flerdosers anordninger har oppmålingsskiver (f.eks. US 5201308 og WO 97/00703) eller oppmå-lingsstempler med en lokal eller kringgående utsparing for å forskyve et visst pul-vervolum fra beholderen til et leveringskammer eller en luftkanal, f.eks. EP 0505321, WO 92/04068 og WO 92/04928. They consist of a relatively large container and a dose measurement unit that must be operated by the patient. The container carries several doses which are isolated individually from the powder bulk by volumetric displacement. Various dose measuring devices exist, including rotatable membranes (eg EP0069715) or plates (eg GB 2041763; EP 0424790; DE 4239402 and EP 0674533), rotatable cylinders (eg EP 0166294; GB 2165159 and WO 92 /09322) and rotatable truncated cones (eg WO 92/00771), all of which have cavities which must be filled with powder from the container. Other multi-dose devices have metering discs (eg US 5201308 and WO 97/00703) or metering pistons with a local or circumferential recess to displace a certain volume of powder from the container into a delivery chamber or air channel, eg. EP 0505321, WO 92/04068 and WO 92/04928.

Reproduserbar doseoppmåling er en av hovedbekymringene for flerdosers inha-latoranordninger. Reproducible dose measurement is one of the main concerns for multi-dose inhaler devices.

Pulverformuleringen må oppvise gode og stabile flytegenskaper, ettersom oppfyl-lingen av dosemålekoppene eller -hulrommene hovedsakelig skjer under innvirk-ningen av tyngdekraften. The powder formulation must exhibit good and stable flow properties, as the filling of the dose measuring cups or cavities mainly occurs under the influence of gravity.

For gjenoppfylte enkeltdose- og flerenhetsdoseinhalatorer, kan produsenten garan-tere for nøyaktigheten og reproduserbarheten av doseoppmålingen. Flerdoseinhalatorer kan, på den andre side, inneholde et meget større antall doser, mens antallet håndgrep for å prime en dose generelt er mindre. For refilled single-dose and multi-unit dose inhalers, the manufacturer can guarantee the accuracy and reproducibility of the dose measurement. Multi-dose inhalers, on the other hand, can contain a much larger number of doses, while the number of hand movements to prime a dose is generally smaller.

Ettersom inhalasjonsluftstrømmen i flerdoseanordningen ofte forløper rett over do-seoppmålingshulrommet, og ettersom de massive og stive doseoppmålingssyste-mer i flerdoseinhalatorer ikke kan forflyttes av denne innsugde luftstrøm, fanges pulvermassen helt enkelt opp fra hulrommet, og det finner sted lite deagglomera-sjon under utstøtningen. As the inhalation airflow in the multi-dose device often runs directly over the dose measurement cavity, and as the massive and rigid dose measurement systems in multi-dose inhalers cannot be moved by this sucked-in airflow, the powder mass is simply captured from the cavity, and little deagglomeration takes place during ejection.

Dermed er det nødvendig med en atskilt desintegrasjonsanordning. I praksis er denne imidlertid ikke alltid del av inhalatordesignet. På grunn av det høye antall doser i flerdosers anordninger, må pulveradhesjonen på de indre vegger av luftka-nalene og deagglomerasjonsanordningen minimeres og/eller det må være mulig å rengjøre disse delene regelmessig, uten å påvirke restdosene i anordningen. Enkelte flerdosers inhalatorer har éngangs legemiddelbeholdere som kan erstattes etter at det forutbestemte antall doser er blitt inntatt (f.eks. WO 97/000703). For slike halvpermanente flerdosers inhalatorer med énveis legemiddelbeholdere er kravene til å forhindre legemiddeloppsamling enda strengere. Thus, a separate disintegration device is required. In practice, however, this is not always part of the inhaler design. Due to the high number of doses in multi-dose devices, the powder adhesion on the inner walls of the air channels and the deagglomeration device must be minimized and/or it must be possible to clean these parts regularly, without affecting the residual doses in the device. Some multi-dose inhalers have disposable drug containers which can be replaced after the predetermined number of doses have been taken (eg WO 97/000703). For such semi-permanent multi-dose inhalers with one-way drug containers, the requirements to prevent drug accumulation are even stricter.

Foruten anvendelser ved bruk av tørrpulverinhalatorer, kan sammensetningene ifølge oppfinnelsen administreres i aerosoler som fungerer ved hjelp av drivgasser eller ved hjelp av såkalte forstøvere, ved hvis hjelp oppløsninger av farmakologisk aktive substanser kan sprøytes under høyt trykk slik at det dannes en støvsky av inhalerbare partikler. Fordelen med disse forstøvere er at man kan klare seg helt uten drivgasser. In addition to applications using dry powder inhalers, the compositions according to the invention can be administered in aerosols that work with the help of propellant gases or with the help of so-called nebulizers, with the help of which solutions of pharmacologically active substances can be sprayed under high pressure so that a dust cloud of inhalable particles is formed. The advantage of these nebulizers is that you can do without propellant gases.

Slike forstøvere beskrives f.eks. i PCT-patentsøknad nr. WO 91/14468 og den in-ternasjonale patentsøknad nr. WO 97/12687, hvor det her henvises til innholdet derav. Such nebulizers are described e.g. in PCT patent application no. WO 91/14468 and the international patent application no. WO 97/12687, where reference is made here to the content thereof.

Spraysammensetninger for topisk levering til lungene ved inhalasjon kan f.eks. formuleres som vandige oppløsninger eller suspensjoner eller som aerosoler som leveres fra trykksatte pakker, så som en inhalator med oppmålte doser, ved bruk av et egnet drivstoff som er gjort flytende. Aerosolformuleringer som er egnet for inhalasjon, kan være enten en suspensjon eller en oppløsning og inneholder generelt den eller de aktive ingredienser og et egnet drivstoff så som et fluorkarbon eller hydrogenholdig klorfluorkarbon eller blandinger derav, spesielt hydrofluoralkaner, f.eks. diklordifluormetan, triklorfluormetan, diklortetrafluoretan, spesielt 1,1,1,2-tetrafluoretan, 1,1,1,2,3,3,3-heptafluor-n-propan eller en blanding derav. Kulldiok-sid eller en annen egnet gass kan også brukes som drivstoff. Aerosolsammenset-ningen kan være fri for andre eksipienser enn drivstoffet, eller kan valgfritt inneholde ytterligere formuleringseksipienser som er velkjent innen faget, så som overflateaktive midler, f.eks. oleinsyre, eller lecitin og koløsningsmidler, f.eks. etanol. Trykksatte formuleringer blir generelt holdt i en kanister (f.eks. en aluminiumkanis-ter) som er lukket med en ventil (f.eks. en oppmålingsventil), og plassert i en aktuator utstyrt med et munnstykke. Spray compositions for topical delivery to the lungs by inhalation can e.g. formulated as aqueous solutions or suspensions or as aerosols delivered from pressurized packages, such as a metered dose inhaler, using a suitable liquefied propellant. Aerosol formulations suitable for inhalation may be either a suspension or a solution and generally contain the active ingredient(s) and a suitable propellant such as a fluorocarbon or hydrochlorofluorocarbon or mixtures thereof, especially hydrofluoroalkanes, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, especially 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon dioxide or another suitable gas can also be used as fuel. The aerosol composition may be free of excipients other than the fuel, or may optionally contain further formulation excipients which are well known in the art, such as surfactants, e.g. oleic acid, or lecithin and cosolvents, e.g. ethanol. Pressurized formulations are generally held in a canister (eg, an aluminum canister) that is closed with a valve (eg, a metering valve), and placed in an actuator equipped with a nozzle.

Det er ønskelig at legemidler for administrasjon ved inhalasjon har en regulert par-tikkelstørrelse. Den optimale partikkelstørrelse for inhalasjon inn i bronkialsystemet er vanligvis 1-10^m, fortrinnsvis 2-5^m. Partikler med en størrelse over 20^m er når de inhaleres, generelt for store til å nå frem til de små luftveiene. For å oppnå disse partikkelstørrelser, kan størrelsen av partiklene av den aktive ingrediens som produseres, reduseres på konvensjonell måte, f.eks. ved mikronisering eller super-kritiske fluidumteknikker. Den ønskede fraksjon kan atskilles ved luftklassifikasjon eller sikting. Fortrinnsvis er partiklene krystallinske. It is desirable that medicinal products for administration by inhalation have a regulated particle size. The optimum particle size for inhalation into the bronchial system is usually 1-10 µm, preferably 2-5 µm. Particles with a size above 20 µm, when inhaled, are generally too large to reach the small airways. To achieve these particle sizes, the size of the particles of the active ingredient produced can be reduced in a conventional manner, e.g. by micronization or super-critical fluid techniques. The desired fraction can be separated by air classification or sieving. Preferably, the particles are crystalline.

Det å oppnå en høy dosereproduserbarhet med mikroniserte pulvere, er vanskelig på grunn av deres dårlige flytegenskaper og ekstreme agglomerasjonstendens. For å forbedre virkningen av tørrpulversammensetninger, bør partiklene være store mens de befinner seg i inhalatoren, men små når de slippes inn i luftveiene. Derfor bruker man generelt en eksipiens så som melkesukker, mannitol eller glukose. Par-tikkelstørrelsen av eksipiensen vil vanligvis være mye større enn den inhalerte kombinasjonen ifølge foreliggende oppfinnelse. Når eksipiensen er melkesukker, vil den vanligvis foreligge som kvernet melkesukker, fortrinnsvis krystallinsk alfa-laktosemonohydrat. Achieving a high dosage reproducibility with micronized powders is difficult due to their poor flow properties and extreme agglomeration tendency. To improve the efficacy of dry powder compositions, the particles should be large while in the inhaler, but small when released into the respiratory tract. Therefore, an excipient such as milk sugar, mannitol or glucose is generally used. The particle size of the excipient will usually be much larger than the inhaled combination according to the present invention. When the excipient is milk sugar, it will usually be present as ground milk sugar, preferably crystalline alpha-lactose monohydrate.

Trykksatte aerosolsammensetninger vil generelt fylles på kanistere utstyrt med en ventil, spesielt en oppmålingsventil. Kanisterne kan valgfritt belegges med et plast-materiale, f.eks. en fluorkarbonpolymer slik som det beskrives i WO96/32150. Kanisterne vil plasseres i en aktuator tilpasset for bukkal levering. Pressurized aerosol compositions will generally be filled into canisters equipped with a valve, particularly a metering valve. The canisters can optionally be coated with a plastic material, e.g. a fluorocarbon polymer as described in WO96/32150. The canisters will be placed in an actuator adapted for buccal delivery.

Typiske sammensetninger for nasal levering omfatter dem som ble nevnt ovenfor for inhalasjon, og omfatter videre ikke-trykksatte sammensetninger i form av en oppløsning eller suspensjon i et inert vehikkel så som vann, valgfritt i kombinasjon med konvensjonelle eksipienser så som buffere, antimikrobielle midler, mukoadhe-sive midler, tonisitetsmodifiserende midler og viskositetsmodifiserende midler som kan administreres med en nasalpumpe. Typical compositions for nasal delivery include those mentioned above for inhalation, and further include non-pressurized compositions in the form of a solution or suspension in an inert vehicle such as water, optionally in combination with conventional excipients such as buffers, antimicrobial agents, mucoadhe -sive agents, tonicity modifying agents and viscosity modifying agents that can be administered with a nasal pump.

Typiske dermale og transdermale formuleringer omfatter et konvensjonelt vandig eller ikke-vandig vehikkel, f.eks. en krem, salve, losjon eller pasta, eller foreligger i form av medisinplastere, -lapper eller -membraner. Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, e.g. a cream, ointment, lotion or paste, or in the form of medicated plasters, patches or membranes.

Forholdene i hvilke (a) kortikosteroidet og (b) den aktuelle antagonisten av M3-muskarinreseptorer kan brukes ifølge oppfinnelsen, er variable. De aktive substanser (a) og (b) kan eventuelt foreligge i form av sine solvater eller hydrater. Av hengig av valget av forbindelsene (a) og (b), varierer vektforholdene som kan brukes innen rammen for foreliggende oppfinnelse, på grunnlag av de forskjellige mo-lekylvekter av de forskjellige saltformer. De farmasøytiske kombinasjoner ifølge oppfinnelsen kan generelt inneholde (a) og (b) i et vektforhold (b):(a) fra 1:100 til 100:1, fortrinnsvis fra 1:50 til 50:1. The conditions in which (a) the corticosteroid and (b) the relevant antagonist of M3 muscarinic receptors can be used according to the invention are variable. The active substances (a) and (b) may optionally be present in the form of their solvates or hydrates. Depending on the choice of the compounds (a) and (b), the weight ratios that can be used within the scope of the present invention vary, on the basis of the different molecular weights of the different salt forms. The pharmaceutical combinations according to the invention can generally contain (a) and (b) in a weight ratio (b):(a) from 1:100 to 100:1, preferably from 1:50 to 50:1.

De nedenfor angitte vektforhold baserer seg på forbindelse (b) uttrykt som 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]-oktanbromid og kortikosteroidene budesonid og beklometasondipropionat, som er spesielt foretrukne ifølge oppfinnelsen. The weight ratios given below are based on compound (b) expressed as 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2] -octane bromide and the corticosteroids budesonide and beclometasone dipropionate, which are particularly preferred according to the invention.

De farmasøytiske kombinasjoner ifølge oppfinnelsen kan f.eks. inneholde (a) og (b) i tilfellet av budesonid, i et vektforhold (b):(a) fra 1:10 til 50:10, fortrinnsvis fra 1:5 til 10:1, fortrinnsvis fra 1:4 til 5:1, mest foretrukket fra 1:2 til 2:1. The pharmaceutical combinations according to the invention can e.g. contain (a) and (b) in the case of budesonide, in a weight ratio of (b):(a) from 1:10 to 50:10, preferably from 1:5 to 10:1, preferably from 1:4 to 5: 1, most preferably from 1:2 to 2:1.

De farmasøytiske kombinasjoner ifølge oppfinnelsen som inneholder kombinasjonene av (a) og (b), administreres normalt slik at 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid og budesonid foreligger sammen i doser fra 5 til 5000^g, fortrinnsvis fra 10 til 2000^g, mer foretrukket fra 15 til 1000^g, enda bedre fra 20 til 800^g pr. enkeltdose. The pharmaceutical combinations according to the invention containing the combinations of (a) and (b) are normally administered so that 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)- l-azoniabicyclo[2.2.2]octane bromide and budesonide are present together in doses from 5 to 5000 g, preferably from 10 to 2000 g, more preferably from 15 to 1000 g, even better from 20 to 800 g per single dose.

For eksempel, kan i tilfellet av kombinasjoner hvor 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid brukes som (b) og budesonid brukes som (a), kombinasjonene ifølge oppfinnelsen f.eks. inneholde fra 20 til 1000^g 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid og fra 50 til 500^g budesonid. For example, in the case of combinations where 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide can be used as ( b) and budesonide are used as (a), the combinations according to the invention e.g. contain from 20 to 1000 g of 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide and from 50 to 500 ^g budesonide.

For eksempel kan kombinasjonene av aktive substanser ifølge oppfinnelsen inneholde 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid og (a) i tilfellet av beklometasondipropionat, i et vektforhold (b):(a) i området fra ca. 1:100 til 50:1, fortrinnsvis 1:50 til 30:1, fortrinnsvis 1:10 til 20:1, mest foretrukket fra 1:5 til 10:1. For example, the combinations of active substances according to the invention may contain 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide and ( a) in the case of beclomethasone dipropionate, in a weight ratio (b):(a) in the range from about 1:100 to 50:1, preferably 1:50 to 30:1, preferably 1:10 to 20:1, most preferably from 1:5 to 10:1.

De farmasøytiske kombinasjoner ifølge oppfinnelsen som inneholder kombinasjonene av (a) og (b), administreres vanligvis slik at 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid og beklometasondipropionat foreligger sammen i doseringer fra 5 til 5000^g, fortrinnsvis fra 50 til 2000 ug, mer foretrukket fra 100 til 1000 ug, enda mer foretrukket fra 200 til 800 ug pr. enkeltdose. The pharmaceutical combinations according to the invention containing the combinations of (a) and (b) are usually administered so that 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)- 1-azoniabicyclo[2.2.2]octane bromide and beclomethasone dipropionate are present together in dosages from 5 to 5000 µg, preferably from 50 to 2000 µg, more preferably from 100 to 1000 µg, even more preferably from 200 to 800 µg per single dose.

For eksempel, kan i tilfellet av kombinasjoner hvor 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid brukes som (b) og beklometasondipropionat brukes som (a), kombinasjonene ifølge oppfinnelsen f.eks. inneholder fra 20 til 1000^g 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid og fra 20 til 800^g beklometasondipropionat. For example, in the case of combinations where 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide can be used as ( b) and beclometasone dipropionate are used as (a), the combinations according to the invention e.g. contains from 20 to 1000 g of 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide and from 20 to 800 ^g beclomethasone dipropionate.

Det bør forstås at de ovennevnte eksempler på mulige doser som kan anvendes for kombinasjonene ifølge oppfinnelsen, oppgis som dose pr. enkeltanvendelse. Imidlertid bør eksemplene ikke tydes dithen at de utelukker muligheten for å administrere kombinasjonene ifølge oppfinnelsen flere ganger. Avhengig av det medisinske behov, kan pasienter også motta flere inhalative anvendelser. For eksempel kan pasienter motta kombinasjonene ifølge oppfinnelsen eksempelvis to eller tre ganger (f.eks. to eller tre sprut med en pulverinhalator, en MDI osv.) om morgenen på hver behandlingsdag. Idet de ovennevnte doseeksempler skal forstås som doseeksempler pr. enkeltanvendelse (dvs. pr. sprut), fører gjentatt anvendelse av kombinasjonene ifølge oppfinnelsen til flere doser i de ovenfor angitte eksempelvise størrelsesordener. Anvendelse av kombinasjonene ifølge oppfinnelsen kan f.eks. skje én gang daglig, eller avhengig av virkningsvarigheten av det antikolinergiske middel, to ganger daglig, eller én gang hver annen eller hver tredje dag, eller selv "etter behov" (tre eller flere ganger daglig på enkelte dager). It should be understood that the above examples of possible doses that can be used for the combinations according to the invention are stated as dose per single use. However, the examples should not be interpreted as excluding the possibility of administering the combinations of the invention multiple times. Depending on the medical need, patients may also receive multiple inhalation applications. For example, patients may receive the combinations of the invention, for example, two or three times (eg two or three puffs with a powder inhaler, an MDI, etc.) in the morning of each treatment day. As the above dose examples are to be understood as dose examples per single application (i.e. per spray), repeated application of the combinations according to the invention leads to several doses in the above-mentioned exemplary orders of magnitude. Application of the combinations according to the invention can e.g. happen once a day, or depending on the duration of action of the anticholinergic agent, twice a day, or once every two or every three days, or even "as needed" (three or more times a day on some days).

Fortrinnsvis er kombinasjonen inneholdt i enhetsdoseform, f.eks. en tablett, kapsel eller oppmålt aerosoldose, slik at pasienten kan administrere en enkeltdose. Preferably, the combination is contained in unit dosage form, e.g. a tablet, capsule or measured aerosol dose, so that the patient can administer a single dose.

Hver doseringsenhet inneholder med fordel fra 20^g til 1000^g og fortrinnsvis fra 50^g til 400^g M3-antagonist eller et farmasøytisk akseptabelt salt derav, og 1^g til 800^g, og fortrinnsvis fra 20^g til 500^g av et kortikosteroid ifølge oppfinnelsen. Each dosage unit advantageously contains from 20^g to 1000^g and preferably from 50^g to 400^g of M3 antagonist or a pharmaceutically acceptable salt thereof, and 1^g to 800^g, and preferably from 20^g to 500 ^g of a corticosteroid according to the invention.

Mengden av hvert aktive stoff som er nødvendig for å oppnå en terapeutisk virkning, vil så klart variere avhengig av det bestemte aktive stoff, administrasjonsru-ten, individet som skal behandles, og den bestemte forstyrrelse eller sykdom som skal behandles. The amount of each active substance necessary to achieve a therapeutic effect will of course vary depending on the particular active substance, the route of administration, the individual to be treated, and the particular disorder or disease to be treated.

De aktive ingredienser kan administreres fra 1 til 6 ganger daglig, tilstrekkelig til å oppvise den ønskede aktivitet. Fortrinnsvis administreres de aktive ingredienser én eller to ganger daglig. The active ingredients can be administered from 1 to 6 times daily, sufficient to exhibit the desired activity. Preferably, the active ingredients are administered once or twice daily.

Man ser for seg at alle aktive ingredienser skal administreres samtidig, eller i meget kort tidsavstand. Alternativt kan ett eller to aktive stoffer inntas om morgenen og det eller de øvrige senere på dagen. Eller i et annet scenarium, kunne ett eller to aktive stoffer inntas to ganger daglig, og det eller de øvrige én gang daglig, enten samtidig som en av de to-ganger-daglig-doseringene fant sted, eller atskilt. Fortrinnsvis vil minst to av, og mer foretrukket alle, de aktive stoffer inntas sammen og samtidig. Fortrinnsvis vil minst to av, og mer foretrukket alle, de aktive stoffer administreres som en blanding. It is envisaged that all active ingredients will be administered at the same time, or at very short intervals. Alternatively, one or two active substances can be taken in the morning and the others later in the day. Or in another scenario, one or two active substances could be taken twice daily, and the other one or more once daily, either at the same time as one of the twice-daily dosages took place, or separately. Preferably, at least two of, and more preferably all, of the active substances will be taken together and at the same time. Preferably, at least two of, and more preferably all, of the active substances will be administered as a mixture.

Kombinasjonen av aktive substanser ifølge oppfinnelsen administreres fortrinnsvis i form av sammensetninger for inhalasjon levert med hjelp av inhalatorer, spesielt tørrpulverinhalatorer, men imidlertid er en hvilken som helst annen form eller par-enteral eller oral anvendelse mulig. Her utgjør anvendelsen av inhalerte sammensetninger den foretrukne anvendelsesform, spesielt ved terapi av obstruktive lung-esykdommer eller for behandling av astma. The combination of active substances according to the invention is preferably administered in the form of compositions for inhalation delivered by means of inhalers, especially dry powder inhalers, but however any other form or parenteral or oral application is possible. Here, the use of inhaled compositions is the preferred form of use, especially in the therapy of obstructive lung diseases or for the treatment of asthma.

De følgende preparatformer oppgis som formuleringseksempler: The following preparation forms are given as formulation examples:

Eksempel 1 Inhalerbart pulver Example 1 Inhalable powder

Eksempel 2 Inhalerbart pulver Eksempel 3 Inhalerbart pulver Eksempel 4 Inhalerbart pulver Example 2 Inhalable powder Example 3 Inhalable powder Example 4 Inhalable powder

Eksempel 5 Inhalerbart pulver Example 5 Inhalable powder

Eksempel 6 Aerosol Eksempel 7 Aerosol Example 6 Aerosol Example 7 Aerosol

Farmakologisk aktivitet Pharmacological activity

På overraskende måte kan man observere en uventet fordelaktig terapeutisk virkning ved behandling av inflammatoriske eller obstruktive sykdommer i luftveiene hvis 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan-salt brukes med ett eller flere kortikosteroider. I betraktning av denne virkning kan de farmasøytiske kombinasjoner ifølge oppfinnelsen brukes i mindre doser enn hva som ville være tilfellet med de enkelte forbindelser hvis de ble brukt i monoterapi på vanlig måte. Dette reduserer uønskede bivirk-ninger som kan forekomme når f.eks. kortikosteroider administreres. Surprisingly, an unexpectedly beneficial therapeutic effect can be observed in the treatment of inflammatory or obstructive diseases of the respiratory tract if 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)- l-azoniabicyclo[2.2.2]octane salt is used with one or more corticosteroids. In view of this effect, the pharmaceutical combinations according to the invention can be used in smaller doses than would be the case with the individual compounds if they were used in monotherapy in the usual way. This reduces unwanted side effects that can occur when e.g. corticosteroids are administered.

De ovennevnte kombinasjoner er bestemte eksempler på foretrukne utførelser av oppfinnelsen, hvor den aktuelle M3-antagonist kombineres med et kortikosteroid. Disse nye kombinasjoner bringer vesentlige terapeutiske fordeler med hensyn til kombinasjonene av M3-antagonister og et kortikosteroid som allerede er kjent innen faget. The above-mentioned combinations are specific examples of preferred embodiments of the invention, where the relevant M3 antagonist is combined with a corticosteroid. These new combinations bring significant therapeutic advantages over the combinations of M3 antagonists and a corticosteroid already known in the art.

Spesielt gir kombinasjonen av den aktuelle M3-antagonist med et kortikosteroid så som budenosid eller beklometason betraktelig og konsekvent mer inhibering av sammentrekningen av trakealringen som respons på allergener enn en terapeutisk ekvivalent kombinasjon av tiotropiumbromid med budesonid eller beklometason. In particular, the combination of the relevant M3 antagonist with a corticosteroid such as budenoside or beclomethasone produces significantly and consistently more inhibition of tracheal ring contraction in response to allergens than a therapeutically equivalent combination of tiotropium bromide with budesonide or beclomethasone.

De følgende sammenlignende eksempler beskriver de fordelaktige egenskaper av kombinasjoner omfattende 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktanbromid (forbindelse 1). The following comparative examples describe the beneficial properties of combinations comprising 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide ( connection 1).

Materialer og metoder Materials and methods

Hannlige Dunkin-Hartley-marsvin (vekt 380-420 g) fra Harlan Ibérica (St. Feliu de Codines, Spania) ble brukt. De ble huset med fri tilgang til mat og vann, i rom som ble holdt ved 22±2°C i en 12-timers lys/mørke-syklus inntil starten av eksperimentet. Male Dunkin-Hartley guinea pigs (weight 380-420 g) from Harlan Ibérica (St. Feliu de Codines, Spain) were used. They were housed with free access to food and water, in rooms maintained at 22±2°C on a 12-h light/dark cycle until the start of the experiment.

Dyrene ble sensitivisert ved hjelp av to sesjoner med aerosolisering med en opp-løsning av 5 mg/ml ovoalbumin på dagene null og 7 av undersøkelsen. Aerosolise-ringsprosedyren bestod av to 30 sekunders forstøvninger (Efbe-airbrushapparat) med et intervall på 5 minutter hvor dyrene ble holdt i en pleksiglasskasse i 10 minutter regnet fra starten av prosedyren. The animals were sensitized by means of two sessions of aerosolization with a solution of 5 mg/ml ovalbumin on days zero and 7 of the study. The aerosolization procedure consisted of two 30-second atomizations (Efbe airbrush apparatus) with an interval of 5 minutes, where the animals were kept in a Plexiglas box for 10 minutes counted from the start of the procedure.

Mellom dagene 14 og 20 fra starten av eksperimentet ble dyrene avlivet, og tra-kealvevet ble fjernet. Én enkelt trakealring ble skåret ut og suspendert i et organ-bad som inneholdt Krebs' oppløsning. Når det vel var festet på en kraftisometrisk omformer, ble den underkastet en grunnhvilespenning på 1 g, ekvilibrert med en blanding av 5% C02i 02og holdt ved 37°C. Between days 14 and 20 from the start of the experiment, the animals were euthanized and the tracheal tissue was removed. A single tracheal ring was excised and suspended in an organ bath containing Krebs' solution. Once attached to a force isometric transducer, it was subjected to a ground rest tension of 1 g, equilibrated with a mixture of 5% CO 2 in O 2 and maintained at 37°C.

Preparatene fikk ekvilibrere under et tidsrom på ikke mindre enn 60 minutter, og deretter ble vehiklet eller forbindelsen(e) som skulle testes, tilsatt til badet. Først tilsatte man kortikosteroidene (om overhodet), og etter en inkubasjonsperiode på 45 minutter, ble M3-antagonisten tilsatt, hvoretter man lot systemet stå i ytterligere 15 minutter. På dette tidspunkt tilsatte man ovoalbumin (i den endelige konsentrasjon 10 ug/ml i badet) for å utløse sammentrekningsresponsen, som ble målt umiddelbart. The preparations were allowed to equilibrate for a period of not less than 60 minutes, and then the vehicle or compound(s) to be tested was added to the bath. First, the corticosteroids (if any) were added, and after an incubation period of 45 minutes, the M3 antagonist was added, after which the system was allowed to stand for a further 15 minutes. At this point, ovalbumin (at a final concentration of 10 µg/ml in the bath) was added to elicit the contractile response, which was measured immediately.

Sammentrekningsresponsene som ble målt med en kraftisometrisk omformer, ut-trykkes i mg. The contraction responses measured with a force isometric transducer are expressed in mg.

Resultater Results

De erholdte resultater vises i tabell 1. The results obtained are shown in table 1.

Resultatene som sammenfattes i tabell 1 og på fig. 1, viser de følgende virkninger: Budenosid alene gir en konsekvent virkning som inhiberer sammentrekningsresponsen, mens beklometason gir en mindre virkning. Resultatene med budenosid stemmer overens med hva som er rapportert av Persson et al. (Int Arch Allergy Appl Immunol 1989; 88: 381-385), som konkluderte med at budenosid reduserte følsomheten for antigen-induserte IgE-drevne sammentrekninger av marsvins trakealringer. The results summarized in table 1 and in fig. 1, they show the following effects: Budenoside alone produces a consistent effect that inhibits the contractile response, while beclomethasone produces a lesser effect. The results with budenoside agree with what has been reported by Persson et al. (Int Arch Allergy Appl Immunol 1989; 88: 381-385), which concluded that budenoside reduced the susceptibility to antigen-induced IgE-driven contractions of guinea pig tracheal rings.

Når forbindelse 1 kombineres med budesonid, men den respektive inkubasjonstid beholdes, er inhiberingen større enn hva som oppnås med budenosid alene. When compound 1 is combined with budesonide, but the respective incubation time is kept, the inhibition is greater than what is achieved with budenoside alone.

På den andre side, når tiotropium kombineres med budenosid, er inhiberingen noe mindre enn hva som utløses av det steroidale middel alene. On the other hand, when tiotropium is combined with budenoside, the inhibition is somewhat less than that produced by the steroidal agent alone.

Når forbindelse 1 kombineres med beklometason, er den oppnådde inhibering stør-re enn hva som utløses av beklometason alene. When compound 1 is combined with beclomethasone, the inhibition achieved is greater than what is triggered by beclomethasone alone.

Når tiotropium kombineres med beklometason, er den oppnådde inhibering også større enn hva som utløses av det steroidale middel alene, men virkningen er ikke så stor som hva som oppnås med forbindelse 1. When tiotropium is combined with beclomethasone, the inhibition achieved is also greater than that elicited by the steroidal agent alone, but the effect is not as great as that achieved with compound 1.

I hvert tilfelle er de inhibitoriske virkninger som utløses av kombinasjonene av kortikosteroider og forbindelse 1, større enn hva som utløses av kombinasjonene av de samme kortikosteroider og tiotropium. In each case, the inhibitory effects elicited by the combinations of corticosteroids and compound 1 are greater than those elicited by the combinations of the same corticosteroids and tiotropium.

Sammenfattet tyder foreliggende eksperiment på at kombinasjonene av forbindelse 1 med steroidale midler ville inhibere sammentrekningen av trakealringene i aktivt sensitiviserte marsvin som respons på antigen, mer aktivt enn kombinasjonene av tiotropium med de samme steroidale midler. In summary, the present experiment suggests that the combinations of compound 1 with steroidal agents would inhibit the contraction of the tracheal rings in actively sensitized guinea pigs in response to antigen, more actively than the combinations of tiotropium with the same steroidal agents.

Dermed har kombinasjonene ifølge oppfinnelsen terapeutisk fordelaktige egenskaper som gjør dem spesielt godt egnet for behandling av respiratoriske sykdommer i alle slags pasienter. Thus, the combinations according to the invention have therapeutically advantageous properties which make them particularly well suited for the treatment of respiratory diseases in all kinds of patients.

KORT BESKRIVELSE AV TEGNINGENE BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 viser den inhibitoriske virkning på sammentrekningen indusert av antigenet i trakealringer isolert fra ovoalbumin-sensitiviserte marsvin, av kortikosteroider alene eller i kombinasjon med forbindelse 1. Fig. 1 shows the inhibitory effect on the contraction induced by the antigen in tracheal rings isolated from ovalbumin-sensitized guinea pigs, of corticosteroids alone or in combination with compound 1.

Claims (18)

1. Kombinasjon som omfatter (a) et kortikosteroid og (b) en antagonist av M3-muska rin reseptorer som er 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo[2.2.2]oktan, i form av et salt som har et anion X, som er et farmasøytisk akseptabelt anion av en én- eller flerverdig syre.1. Combination comprising (a) a corticosteroid and (b) an antagonist of M3 muscarinic receptors which is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3- phenoxypropyl)-1-azoniabicyclo[2.2.2]octane, in the form of a salt having an anion X, which is a pharmaceutically acceptable anion of a mono- or polyhydric acid. 2. Kombinasjon ifølge krav 1, hvor antagonisten av M3-muskarinreseptoren (b) er 3(R)-(2-hydroksy-2,2-ditien-2-ylacetoksy)-l-(3-fenoksypropyl)-l-azoniabicyklo-[2.2.2]oktanbromid.2. Combination according to claim 1, wherein the antagonist of the M3 muscarinic receptor (b) is 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo- [2.2.2]octane bromide. 3. Kombinasjon ifølge krav 1 eller 2, hvor kortikosteroidet er valgt fra gruppen bestående av deksametason, budesonid, beklometason, triamkinolon, mometason, ciclesonid, fluticason, flunisolid, deksametason-natriumfosfat samt estere derav så vel som 6a,9a-difluor-17a-[(2-furanylkarbonyl)oksy]-lip-hydroksy-16a-metyl-3-oksoandrosta-l,4-dien-17|3-karbotioinsyre (S)-fluormetyl-ester.3. Combination according to claim 1 or 2, where the corticosteroid is selected from the group consisting of dexamethasone, budesonide, beclomethasone, triamquinolone, mometasone, ciclesonide, fluticasone, flunisolide, dexamethasone sodium phosphate and esters thereof as well as 6a,9a-difluoro-17a- [(2-furanylcarbonyl)oxy]-lip-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17|3-carbothioic acid (S)-fluoromethyl ester. 4. Kombinasjon ifølge krav 3, hvor kortikosteroidet er valgt fra gruppen bestående av budesonid, beklometason-dipropionat og mometasonfuroat.4. Combination according to claim 3, where the corticosteroid is selected from the group consisting of budesonide, beclomethasone dipropionate and mometasone furoate. 5. Kombinasjon ifølge krav 4, hvor kortikosteroidet er budesonid.5. Combination according to claim 4, wherein the corticosteroid is budesonide. 6. Kombinasjon ifølge krav 4, hvor kortikosteroidet er beklometason-dipropionat.6. Combination according to claim 4, wherein the corticosteroid is beclomethasone dipropionate. 7. Kombinasjon ifølge krav 4, hvor kortikosteroidet er mometasonfuroat.7. Combination according to claim 4, wherein the corticosteroid is mometasone furoate. 8. Kombinasjon ifølge ethvert av de foregående krav,karakterisert vedat de aktive bestanddeler (a) og (b) danner en del av en enkel farmasøytisk sammensetning.8. Combination according to any of the preceding claims, characterized in that the active ingredients (a) and (b) form part of a single pharmaceutical composition. 9. Kombinasjon ifølge ethvert av de foregående krav, som ytterligere omfatter (c) en annen aktiv forbindelse valgt fra: (a) PDE IV-inhibitorer, (b) p2-agonister, (c) leukotrien D4-antagonister, (d) inhibitorer av egfr-kinase, (e) p38 kinase-inhibitorer og (f) NK1 reseptor-agonister.A combination according to any one of the preceding claims, further comprising (c) another active compound selected from: (a) PDE IV inhibitors, (b) β2 agonists, (c) leukotriene D4 antagonists, (d) inhibitors of egfr kinase, (e) p38 kinase inhibitors and (f) NK1 receptor agonists. 10. Kombinasjon ifølge krav 9, hvor den aktive forbindelse (c) er valgt fra gruppen bestående av (a) PDE IV-inhibitorer og (b) p2-agonister.10. Combination according to claim 9, wherein the active compound (c) is selected from the group consisting of (a) PDE IV inhibitors and (b) β2 agonists. 11. Anvendelse av (a) et kortikosteroid som angitt i ethvert av kravene 1 og 3 til 7 og (b) en antagonist av M3 muskarine reseptorer som angitt i krav 1 eller 2, for fremstilling av et medikament for samtidig, parallell, separat eller sekvensiell anvendelse ved behandling av en respiratorisk sykdom som reagerer på M3-antagonist i en pasient.11. Use of (a) a corticosteroid as set forth in any of claims 1 and 3 to 7 and (b) an antagonist of M3 muscarinic receptors as set forth in claim 1 or 2, for the manufacture of a medicament for simultaneous, parallel, separate or sequential use in the treatment of a respiratory disease responsive to M3 antagonist in a patient. 12. Anvendelse ifølge krav 11, hvor den respiratoriske sykdommen er astma eller kronisk obstruktiv lungesykdom (KOLS).12. Use according to claim 11, where the respiratory disease is asthma or chronic obstructive pulmonary disease (COPD). 13. Produkt omfattende (a) kortikosteroid som angitt i ethvert av kravene 1 og 3 til 7 og (b) en antagonist av M3-muskarinreseptorer ifølge kravene 1 eller 2, som et kombinasjonspreparat for simultan, parallell, separat eller sekvensiell bruk ved behandling av en pasient som lider av eller er tilbøyelig for en respiratorisk sykdom som angitt i kravene 11 eller 12.13. Product comprising (a) corticosteroid as stated in any of claims 1 and 3 to 7 and (b) an antagonist of M3 muscarinic receptors according to claims 1 or 2, as a combination preparation for simultaneous, parallel, separate or sequential use in the treatment of a patient suffering from or prone to a respiratory disease as specified in claims 11 or 12. 14. Produkt ifølge krav 13, som ytterligere omfatter en aktiv forbindelse (c) som angitt i krav 9 eller 10.14. Product according to claim 13, which further comprises an active compound (c) as stated in claim 9 or 10. 15. Pakke omfattende (b) en antagonist av M3-muskarinreseptorer ifølge krav 1 eller 2 og (a) et kortikosteroid som angitt i ethvert av kravene 1 og 3 til 7 for samtidig, parallell, atskilt eller sekvensiell bruk ved behandling av en respiratorisk sykdom som angitt i krav 11 eller 12.15. A kit comprising (b) an antagonist of M3 muscarinic receptors according to claim 1 or 2 and (a) a corticosteroid as set forth in any of claims 1 and 3 to 7 for simultaneous, parallel, separate or sequential use in the treatment of a respiratory disease as stated in claim 11 or 12. 16. Pakke ifølge krav 17, som ytterligere omfatter en aktiv forbindelse (c) som angitt i krav 9 eller 10.16. Package according to claim 17, which further comprises an active compound (c) as stated in claim 9 or 10. 17. Anvendelse av (b) en antagonist av M13 muskarine reseptorer som angitt i krav 1 eller 2, for fremstilling av et medikament for samtidig, parallell, separat eller sekvensiell anvendelse i kombinasjon med (a) et kortikosteroid som angitt ethvert av kravene 1 og 3 til 7, for behandling av en respiratorisk sykdom som angitt i krav 11 eller 12.17. Use of (b) an antagonist of M13 muscarinic receptors as stated in claim 1 or 2, for the preparation of a medicament for simultaneous, parallel, separate or sequential use in combination with (a) a corticosteroid as stated in any of claim 1 and 3 to 7, for the treatment of a respiratory disease as stated in claim 11 or 12. 18. Anvendelse av (a) et kortikosteroid som angitt i krav 1 og 3 til 7, for fremstilling av et medikament for samtidig, parallell, separat eller sekvensiell anvendelse i kombinasjon med (b) en antagonist av M3 muskarine reseptorer som angitt i krav 1 eller 2, for behandling av en respiratorisk sykdom som angitt i krav 11 eller 12.18. Use of (a) a corticosteroid as stated in claims 1 and 3 to 7, for the preparation of a medicament for simultaneous, parallel, separate or sequential use in combination with (b) an antagonist of M3 muscarinic receptors as stated in claim 1 or 2, for the treatment of a respiratory disease as stated in claim 11 or 12.
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